Epstein Barr virus (EBV) is the cause of infectious mononucleosis and is associated with a number of cancers including Hodgkin's disease and Burkitt's lymphoma. Chronic active EBV is a rare disease in which persons have persistent organ disease due to the virus. We are studying patients with chronic active EBV virus to try to determine the cause of this disease. Since some patients with chronic active EBV have been reported to have defects in killing of target cells by their white blood cells, we have focused on proteins important for this activity. Perforin is important for killing of virus-infected cells by T cells or natural killer cells. We identified novel mutations in both copies of the perforin gene in a patient who died with chronic active EBV. The patient had a very low level of the perforin protein in his white blood cells compared with healthy blood donors, and his cells expressed only an immature form of perforin. The patients cells were impaired for their ability to kill target cells. EBV is also associated with lymphoproliferative disease and lymphomas in patients with impaired immune systems, such as those with AIDS. These tumors contain EBV-transformed B cells. We found that treatment of EBV-transformed B cells in cell culture with simvastatin, a drug that is used to treat elevated cholesterol, resulted in programmed cell death (apoptosis). Immunodeficient mice inoculated with EBV-transformed B cells develop B cell lymphomas similar to those seen in patients with AIDS. Administration of simivastatin to immunodeficient mice followed by inoculation with EBV-transformed B cells resulted in delayed development of lymphomas and prolonged survival of the animals.